The present invention relates to a novel process for the production of 3-alkoxymethyl cephalosporin derivatives, and in particular 7-amino-3-alkoxymethyl-3-cephem-4-carboxylic acid compounds and salts thereof.
7-Amino-3-alkoxymethyl-3-cephem-4-carboxylic acids, i.e. compounds of formula (I): ##STR2## wherein R is an alkyl group, and salts thereof are known compounds which are important intermediates in the preparation of the cephalosporin antibiotics.
Many processes are already known for the preparation of these 7-amino-3-alkoxymethyl-3-cephem-4-carboxylic acid compounds. Most of these processes use as their main starting material the known compound, 7-ACA, which is also commonly called 7-aminocephalosporanic acid or 7-amino-3-acetoxymethyl-3-cephem-4-carboxylic acid and has the formula (II): ##STR3##
However, each of these known processes has its own problems, for example each yields only moderate quantities of the desired product. A large amount of by-products are produced during these processes due to the production of lactone compounds (resulting from the cyclisation of the carboxy group and the 3-position acetoxymethyl group of the starting material 7-ACA) or due to the decomposition of the .beta.-lactam ring. These by-products reduce the yield and interfere with the purification process. p1 1. In European Patent Publication No. 204657, 7-ACA is reacted with a lower alcohol in the presence of boron trifluoride or a complex thereof.
2. In European Patent Publication No. 262744, 7-ACA is reacted with a lower alcohol in the presence of, for example, a halide of antimony or zinc. PA1 4. In Japanese Patent Application Kokai No. 63-115887, 7-ACA is reacted with a lower alcohol compound and a boron trifluoride-lower alcohol complex, a halosulfonic acid or a halogen-substituted or unsubstituted alkyl sulfonic acid.
3. In Japanese Patent Application Kokai No. 59-163387, 7-ACA is reacted with a lower alcohol and a sulfonic acid. The acid acts as catalyst and is present in excess quantities relative to the 7-ACA.
The closest prior art, however, appears to be European Patent Publication No. 343926 which describes the reaction of 7-ACA with a protonic acid or a Lewis acid, or borate complex thereof, and an ortho-organic acid ester or acetal. Protonic acids which are stated to be suitable for this reaction are aryl- or alkylsulfonic acids, sulfuric acid or halosulfuric acids However, although this process may be used for the preparation of these important intermediates of formula (I), the yield of the product is fairly low due to the simultaneous production of large amounts of by-products, produced by the production of lactone compounds or the decomposition of the .beta.-lactam ring.